Recent advances in molecular immunology have allowed researchers to obtain a detailed view of the cellular and molecular events which take place during the human immune response to pathogenic infection. In addition to determining the roles of the various lymphocytes in the immune response, researchers have also made some progress in mapping out their biochemical interactions, including those that involve macromolecules which may act as chemical signals to coordinate lymphocyte actions and functions.
The modern view of immunology has the T-cell as a key player in the body's specific defense mechanism. Two particular classes of T-cells, the helper T-cell (T.sub.H) and the cytotoxic T-cell (T.sub.C), play important roles in the both the humoral and the cell-mediated immune response. In contrast, B-lymphocytes are exclusively involved in the humoral immune response.
The humoral response is usually directed against free circulating pathogens or their antigens. Antigen-Presenting cells (APCs), such as macrophages, express fragments of digested antigens on their outer membranes often in combination with Class II MHC (Major Histo-Compatibility) proteins. Recognition of these Class II MHCs and foreign antigens trigger T.sub.H cells to proliferate. This, in turn, triggers B-cells to secrete antibodies which eventually neutralize the pathogens.
The cell-mediated response involves participation by both T.sub.H and T.sub.C cells. In this case, a cell of the body infected by the pathogen displays pathogen antigens in combination with Class I MHC proteins and thereby stimulates T.sub.H cells to activate T.sub.C cells which lyse the infected cell. [See Biology (3rd. ed.) Campbell, Benjamin Cummings Publishing Company, Inc. (1993)].
Because of the critical role played by the T-cells in the body's defense systems, the destruction of certain T-cell populations by the AIDS virus, effectively robs the body of its ability to defend itself. AIDS therapies have therefore focused on ways to prevent T-cell destruction and/or regenerate T-cell function. Such efforts have thus far been hampered by a lack of complete understanding of T-cell biochemistry including the elaboration of soluble mediators, i.e., cytokines.
There have been numerous studies of both biochemical mediators and cellular interactions which cause the stimulation and thereby proliferation of the body's T-cells. Much of the work has centered on discovering the identity of both the chemical signals and the membrane receptors which are directly responsible. [See Lanier "Distribution and Function of Lymphocyte Surface Antigens" Ann. N.Y. Acad. Sci. 677:86 (1993)].
It is generally agreed that T-cell activation requires more than just binding of the T-cell receptors (TCRs) to specific antigen/MHC protein combinations. [See Biology (3rd. ed.) Campbell, Benjamin Cummings Publishing Company, Inc. (1993)]. In particular, there has been much research on the existence of additional molecular binding events, in effect a "costimulatory" signal. These costimulatory signals, although not antigen-specific, have been shown to be critical for many stages of T-cell development, activation, and proliferation. [See Mizel "Characterization of Lymphocyte Activating Factor (LAF) Produced by Macrophage Cell Line" J. Immunol 120:1504 (1978)].
Recent immunological research has focused on two types of costimulatory signals. The first class of costimulatory signals are macromolecules which freely diffuse through the intercellular medium, where they bind to receptors on the exterior membrane of the T-cell, causing the desired metabolic changes. These free costimulators are themselves typically secreted by other lymphocytes. Shaw et al. were among the first to describe a factor, designating it by the term "Costimulator". The molecule behaved like a nonspecific second signal to induce the proliferation of T-cells, following the first signal which is an antigen. [See "Effects of Costimulator on Immune Responses IN VITRO," J. Immun. 120:1974 (1978)]. Teh et al. describe the use of the same "Costimulator" in a model system to activate cytotoxic T-cells, which were initially stimulated by antigen. [See "Direct Evidence for a Two-Signal Mechanism of Cytotoxic T-Lymphocyte Activation," Nature 285:163 (1980)]. This was also corroborated by Shaw et al. [See "Cellular Origins of Co-stimulator (IL2) and Its Activity in Cytotoxic T Lymphocyte Responses," J. Immun. 124:2231 (1980)].
"Costimulators" and other related compounds are generally peptides referred to under the general category of "Interleukins". It is currently uncertain whether compounds outside the Interleukin family can elicit T-cell metabolic changes as well. A recent article by Chouaib describes the use of purified Tumor Necrosis Factor (TNF) in the costimulation of cytotoxic cell differentiation. [See "Tumor Necrosis Factor a: a Costimulator for Cytotoxic Cell Differentiation," Nouv. Rev. Fr. Hematol. 33:471 (1991)]. However, this compound only works in combination with interleukin-2, which has the ability to stimulate T-cells without the participation of another nonspecific molecule.
A second class of costimulatory signals under investigation are membrane bound ligands typically found on other APCs, which bind to receptor proteins on the T-cell surface. In particular, there has been considerable research focused on the CD28 receptor present on the outer membrane of T-cells. [See Jenkins et al. "CD28 Delivers a Costimulatory Signal Involved in Antigen-Specific IL-2 Production By Human T Cells," J. Immun. 147:2461 (1991) and Fraser et al. "Regulation of T-cell Lymphokine Gene Transcription by the Accessory Molecule CD28," Mol. & Cell. Bio. 10:4357 (1992)]. This receptor and its activation ligand present on B-lymphocytes, "B7/BB1," may play a pivotal role in T-cell activation through regulation of their cytokine gene transcription. [See Koulova et al. "The CD28 Ligand B7/BB1 Provides Costimulatory Signal for Alloactivation of CD4+ TCells," J. Exp. Med 173:759 (1991), Gross et al. "Identification and Distribution of the Costimulatory receptor CD28 in the Mouse," J. Immun 149:380 (1992), and Larsen et al. "Functional Expression of the Costimulatory Molecule B7/BB1, on Murine Dendritic Cell Populations," J. Exp. Med 176:1215 (1992)].
While purified B7/BB1 may be a viable T-cell stimulator, it is a complex protein of high molecular weight, and can only be produced in large quantities through recombinant DNA techniques. It is clear that there would be a usefulness for a simpler costimulator that can be synthesized chemically.